Procaterol-containing preparation for application to the skin

ABSTRACT

A procaterol-containing preparation for application to the skin which comprises a drug-retaining layer provided on a support, wherein said drug-retaining layer comprises a substantially water-free adhesive gel base comprising as essential components polyacrylic acid, a crosslinking agent and at least one lower alcohol or polyvalent alcohol, and 0.1 to 5% by weight of procaterol or a pharmaceutically acceptable salt thereof. Said preparation for application to the skin can be used as an external preparation for application to the skin which is capable of stably delivering procaterol or a salt thereof through the skin for a long time of period.

TECHNICAL FIELD

The present invention relates to a procaterol-containing externalpreparation for application to the skin. More particularly, the presentinvention relates to an external preparation for application to the skinwhich comprises as active ingredients procaterol or a pharmaceuticallyacceptable salt thereof which is dissolved in an alcohol dispersedly ina substantially water-free polyacrylic acid gel, said preparation beingcapable of stably delivering said active ingredient through the skin fora long period of time.

BACKGROUND ART

Procaterol is known as a bronchodilator which stimulates the β-receptorof sympathetic nerves and shows strong bronchodilating activity in verysmall amounts. The duration of the activity of procaterol is long (8hours or more), and hence, procaterol is an excellent drug from theviewpoint of duration of time and absorbability.

This drug is generally used in the form of a hydrochloride salt andorally administered in the form of tablets, granules, syrups oradministered by inhalation in the form of inhalants or aerosols.

The present inventors have tried to transdermally administer procaterolin the form of conventional cataplasms or tapes in order to externallyapply procaterol. However, the present inventors have found that such apreparation for application to the skin has the following disadvantages:

(1) The cataplasms should contain a fixed amount of a drug in a base sothat the desired activity of the drug is exhibited. However, since thecataplasms is usually applied in a large amount (1,000 to 1,500 g/m²),the drug present at the deep portion within the base moves hardly to thesurface and is hardly absorbed, and as a result, the availability of thedrug is lowered. Therefore, in case of a drug having a strongbronchodilating activity in a very small amount like procaterol, it isnot preferable because of remaining of the drug within the base.

(2) On the other hand, when an aqueous base like the base for cataplasmsis spread in such a thin layer as 50 to 300 g/m², it results in adecreased adhesiveness and an increased evaporation of water, which isnot preferable in viewpoint of the properties required for thepreparation for application to the skin.

(3) Procaterol can be used in the form of tapes. However, procaterolshows a strong interaction with the base of tapes, which is notpreferable in viewpoint of the delivery and availability of the drug.

Under the circumstances, the present inventors have intensively studiedfor developing an improved preparation for application to the skinsuitable for transdermal administration of procaterol. As a result, thepresent inventors have found that a quite novel preparations forapplication to the skin can be obtained by incorporating procaterol intoa substantially water-free adhesive gel base prepared by dissolvingpolyacrylic acid in an alcohol and crosslinking polyacrylic acid with acrosslinking agent, and then have completed the present invention. Thepreparation of the present invention has the following characteristics:

(1) Since the preparation of the present invention contains a largeramount of alcohol in the base than that of conventional tapes orcataplasms, the drug is easily dissolved and dispersedly kept in thebase, and hence, there can be prepared a base which allows an excellentdrug delivery even when a small amount of the drug is contained in thebase;

(2) Polyacrylic acid used in the base inhibits the decomposition of thedrug, allowing a stable storage of the drug for a long period of time;

(3) Since the drug dissolved is dispersedly retained within the adhesivegel base, the drug is delivered to the skin at a constant rate, allowinga continuous transdermal absorption;

(4) Since the base contains substantially no water, it is stable andhardly denatured when applied to the skin or during storage; and

(5) The preparation of the present invention has moderate adhesiveness,and hence, can be thinly applied. In addition, the preparation of thepresent invention does not cause pain when peeled off.

DISCLOSURE OF THE INVENTION

That is, the present invention provides a procaterol-containing externalpreparation for application to the skin which comprises a drug-retaininglayer provided on a support, wherein said drug-retaining layer comprisesan adhesive gel base comprising as essential components polyacrylicacid, a cross-linking agent and at least one lower alcohol or polyvalentalcohol, and 0.1 to 5% (.% by weight, hereinafter the same) ofprocaterol or a pharmaceutically acceptable salt thereof. Procaterol iscontained in the network structure formed by the crosslinking agent withpolyacrylic acid in the state of being dispersedly dissolved in thelower alcohol or polyvalent alcohol.

Polyacrylic acid used in the preparation for application to the skin ofthe present invention retains the lower alcohol or polyvalent alcoholwhich contains procaterol dissolved therein and provides a stabledelivery of procaterol at the surface in contact with the skin.Polyacrylic acid also provides adhesiveness for the preparation, andhence, there can be obtained a preparation for application to the skinwhich has an excellent adhesiveness even when the base is appliedthinly. Polyacrylic acid may be commercially available ones, preferablythose having a viscosity of 5,000 to 150,000 cps at 25° C. in a 10%aqueous solution.

The above polyacrylic acid is usually contained in the adhesive gel basein an amount of 1 to 20%, preferably 3 to 15%. When the amount ofpolyacrylic acid is less than 1%, the desired three-dimensional networkstructure is not sufficiently formed and the formed gel becomes feeble.On the other hand, when the amount of polyacrylic acid is more than 20%,the drug-retaining layer becomes too hard, which results in a decreasedadhesiveness or inhibition of transfer of the drug to the skin.

The crosslinking agent is used for crosslinking the above-mentionedpolyacrylic acid dissolved in the lower alcohol or polyvalent alcohol toform a three-dimensional network structure to endow the base with a heatresistance so that the base does not melt out of the preparation whenapplied to human beings or during storage. The crosslinking agent usedin the present invention includes aluminum salts and magnesium saltssuch as aluminum chloride, aluminum sulfate, aluminum potassiumsulfate,ammonium aluminum sulfate, magnesium aluminate silicate, magnesiumaluminate metasilicate, dihydroxy aluminum acetate and the like, whichmay be used alone or in combination of two or more thereof. Thecrosslinking agent is usually used in an amount of 0.01 to 7%,preferably 0.01 to 5%, based on the amount of the adhesive gel base.

The lower alcohol or polyvalent alcohol acts as an agent for dissolvingprocaterol and/or the above-mentioned water-soluble high molecularweight compound or an agent for promoting drug delivery and includes,for example, lower alcohols such as ethanol, propanol, and the like; andpolyvalent alcohols such as lower alkylene glycols (e.g. ethyleneglycol, propylene glycol, 1,3-butanediol, 3-methyl-1,3-butanediol, andthe like), poly(lower)alkylene glycols (e.g. polyethylene glycol,polypropylene glycol, and the like), glycerol, and the like, which maybe used alone or in combination of two or more thereof. The "lower"alcohol in the specification means a C₁ -C₄ alcohol.

The above-mentioned lower alcohol or polyvalent alcohol is usually usedin an amount of 50 to 95%, preferably 55 to 90% based on the amount ofthe adhesive gel base. When the amount is less than 50%, the alcoholscan not show the desired function as the agent for dissolving theabove-mentioned water-soluble high molecular weight compound, and hence,the gel base shows an increased viscosity and becomes difficult tohandle with. On the other hand, when the amount is more than 95%,amounts of the other components becomes excessively low, and as aresult, basic characteristics of the preparation for application to theskin such as adhesiveness, shape retention, heat resistance, and thelike cannot be obtained.

Polyacrylic acid or the crosslinking agent usually contains impuritiessuch as a heavy metal or an ion thereof (e.g. aluminum, magnesium, orion thereof). Accordingly, in order to promote the continuousdecomposition of procaterol, the base may contain a sequestering agentto chelate the heavymetal, thereby stably preserving procaterol for along period of time. The sequestering agent includes a conventionalchelating agent capable of forming a chelate with the heavy metal or anion thereof, including EDTA, a pharmaceutically acceptable salt of EDTAsuch as EDTA 2Na, polyphosphoric acid, a pharmaceutically acceptablesalt of polyphosphoric acid such as potassium polyphosphate. Thesequestering agent is used in an amount of 0.001 to 0.1% based on theamount of adhesive gel base.

As mentioned above, the adhesive gel base comprises polyacrylic acid, acrosslinking agent, and at least one lower alcohol or polyvalent alcoholas essential components. The adhesive gel base may further optionallycontain a conventional high molecular weight compound, for example,sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone,polyethylene oxide, sodium alginate, gelatine, dextrin, karaya gum,starch, etc., which is usually used in an amount of 0.01 to 7%,preferably 0.1 to 5%, based on the amount of the adhesive gel base.

The adhesive gel base may further optionally contain a conventional drugabsorption-promoting agent (e.g. isopropyl myristate, isopropylpalmitate, N-methylpyrrolidone, N-ethylpyrrolidone,N,N-diethyl-m-toluamide, N,N-dimethylacetamide, hyaluronic acid,salicylic acid, chrotamiton, diethyl sebacate, lauryl alcohol, and thelike) so that the drug is absorbed more efficiently. Theabsorption-promoting agent is used in an amount of 0.1 to 20% by weight,preferably 0.1 to 15% by weight, based on the amount of the adhesive gelbase.

The amount of procaterol in the preparation is preferably determinedunder taking into consideration the application amount of the adhesivegel base so as to achieve high utilization degree of the drug. Generallyspeaking, it is preferred that the adhesive gel base is thinly appliedto the skin and has a high concentration of the drug. From this point ofview, procaterol is preferably contained in the adhesive gel base in anamount of 0.1 to 5%. When the amount is less than 0.1%, the activity ofthe drug cannot efficiently be exhibited. On the other hand, when theamount is more than 5%, the crosslinking of the base is inhibited andthe heat resistance of the base becomes poor. Even if the adhesive gelbase contains procaterol in an excessive amount, the drug is noteffectively utilized and the activity of the drug is not improved, whichis disadvantageous also from economical viewpoint.

The procaterol-containing preparation for application to the skin of thepresent invention can be prepared by dissolving polyacrylic acid in analcohol with heating, cooling the solution, adding procaterol and othercomponents thereto, and further adding a crosslinking agent thereto toprepare the adhesive gel base. The obtained adhesive gel base is thenapplied to a suitable support and laminate the surface with a liner toprepare a drug-retaining layer. The adhesive gel base is applied in anamount of less than 300 g/m², preferably 50 to 250 g/m².

The support used in the preparation of the invention is preferably madeof a flexible thin material which fits for the movement of human body inorder to prevent undesirable peeling when applied to the skin. Thematerial used for the support includes, for example, various non-wovenfabrics, woven fabrics, flannel, spandex, or a laminate thereof withpolyethylene film, ethylene vinyl acetate film, polyurethane film, andthe like.

The procaterol-containing preparation for application to the skin of thepresent invention prepared as mentioned above has the followingcharacteristics:

(1) Since the preparation of the present invention contains a largeramount of alcohol in the base than that of conventional tapes orcataplasms, the drug is easily dissolved and dispersedly kept in thebase, and hence, there can be prepared a base which shows an excellentdrug delivery even when a small amount of the drug is contained in thebase;

(2) Polyacrylic acid used in the base inhibits undesirable decompositionof the drug, allowing a stable storage of the drug for a long period oftime;

(3) Since the drug dissolved is dispersedly retained within the adhesivegel base, the drug is delivered to the skin at a constant rate, allowinga continuous transdermal absorption;

(4) Since the base contains substantially no water, it is stable andhardly denatured when applied to the skin or during storage; and

(5) The preparation of the present invention has a moderateadhesiveness, and hence, can be thinly applied. In addition, thepreparation of the present invention does not cause pain when peeled offunlike tape preparation.

BRIEF EXPLANATION OF THE DRAWINGS

FIG. 1 is a graph showing a relationship between the time afterapplication and the amount of procaterol hydrochloride which ispermeated through the skin in the preparations for application to theskin prepared in Examples of the present invention and ComparativeExample;

FIG. 2 is a graph showing a relationship between the time afterapplication and the inhibitory rate of bronchocontractile activity ofhistamine by procaterol.

BEST MODE FOR CARRYING OUT THE INVENTION

The preparation for application to the skin of the present invention isexplained in more detail by means of Examples and Comparative Exampleshereinbelow but should not be construed to be limited thereto.

EXAMPLE 1

    ______________________________________                                        [Component]              [% (w/w)]                                            ______________________________________                                        Polyacrylic acid (trade name Julimer                                                                   7                                                    AC-10HP manufactured by Nippon Junyaku                                        K.K.)                                                                         Magnesium aluminate metasilicate                                                                       2.5                                                  Procaterol hydrochloride 0.5                                                  Propylene glycol         30                                                   EDTA 2Na                 0.01                                                 Ethanol                  10                                                   Glycerol                 q.s                                                  Total                    100                                                  ______________________________________                                    

Polyacrylic acid is dissolved in glycerol with heating at about 100° C.After cooling, thereto are added procaterol hydrochloride dissolved inpropylene glycol and then the remaining components successively, and themixture is stirred to give an adhesive base. Then, the adhesive gel basewas applied to a support which is a laminate of non-woven fabric made ofrayon and ethylene vinyl acetate film in an amount of 200 g/m². To thesurface was adhered a liner made of polyethylene terephthalate filmprocessed with silicone. The obtained preparation is cut into a desiredsize to give an external preparation for application to the skin(containing 100 μg/cm² of procaterol hydrochloride).

EXAMPLE 2

    ______________________________________                                        [Component]               [% (w/w)]                                           ______________________________________                                        Polyacrylic acid          4                                                   Polyvinyl pyrrolidone (trade name PVP K-90                                                              2                                                   manufactured by G.A.F. CORPORATION)                                           Propylene glycol          30                                                  Dihydroxy aluminum acetate                                                                              1                                                   Aluminum potassium sulfate                                                                              1.5                                                 Procaterol hydrochloride  0.5                                                 EDTA 2Na                  0.01                                                Glycerol                  q.s                                                 Total                     100                                                 ______________________________________                                    

Using the above components, the procedures in Example 1 are repeated togive an external preparation for application to the skin (containing 100μg/cm² of procaterol hydrochloride).

EXAMPLE 3

    ______________________________________                                        [Component]               [% (w/w)]                                           ______________________________________                                        Polyacrylic acid          3                                                   Polyvinyl alcohol (trade name Gosenol NH-26                                                             3                                                   manufactured by the Nippon Synthetic                                          Chemical Industry Co., Ltd.)                                                  Propylene glycol          20                                                  Magnesium aluminate metasilicate                                                                        3                                                   Aluminum chloride         0.5                                                 Procaterol hydrochloride  1                                                   EDTA 2Na                  0.01                                                N,N-diethyl-m-toluamide   1                                                   Glycerol                  q.s                                                 Total                     100                                                 ______________________________________                                    

Using the above components, the procedures in Example 1 are repeatedexcept that the adhesive gel base is applied to the support at 100 g/m²to give an external preparation for application to the skin (containing100 μg/cm² of procaterol hydrochloride).

EXAMPLE 4

    ______________________________________                                        [Component]           [% (w/w)]                                               ______________________________________                                        Polyacrylic acid      7.04                                                    Magnesium aluminate metasilicate                                                                    0.5                                                     Alum                  0.3                                                     Propylene glycol      36.2                                                    N,N-diethyl-m-toluamide                                                                             5                                                       N,N-dimethylacetamide 10                                                      EDTA 2Na              0.01                                                    Procaterol hydrochloride                                                                            1                                                       Glycerol              q.s                                                     Total                 100                                                     ______________________________________                                    

Using the above components, the procedures in Example 1 are repeated togive an external preparation for application to the skin (containing 200μg/cm² of procaterol hydrochloride).

EXAMPLE 5

    ______________________________________                                        [Component]           [% (w/w)]                                               ______________________________________                                        Polyacrylic acid      6                                                       N,N-dimethylacetamide 10                                                      Magnesium aluminate metasilicate                                                                    3                                                       Procaterol hydrochloride                                                                            1                                                       Propylene glycol      20                                                      EDTA 2Na              0.01                                                    Glycerol              q.s                                                     Total                 100                                                     ______________________________________                                    

Using the above components, the procedures in Example 1 are repeated togive an external preparation for application to the skin (containing 200μg/cm² of procaterol hydrochloride).

EXAMPLE 6

    ______________________________________                                        [Component]           [% (w/w)]                                               ______________________________________                                        Polyacrylic acid      6                                                       N,N-dimethylacetamide 10                                                      Magnesium aluminate metasilicate                                                                    3                                                       Procaterol hydrochloride                                                                            1                                                       Propylene glycol      20                                                      Glycerol              q.s                                                     Total                 100                                                     ______________________________________                                    

Using the above components, the procedures in Example 1 are repeated togive an external preparation for application to the skin (containing 200μg/cm² of procaterol hydrochloride).

COMPARATIVE EXAMPLE 1

    ______________________________________                                        [Component]              [% (w/w)]                                            ______________________________________                                        Adhesive agent of emulsion type (copolymer                                                             120                                                  of methyl acrylate and 2-ethylhexyl                                           acrylate, solid content 60%)                                                  Glycerol                  25                                                  N,N-diethyl-m-toluamide   1                                                   Procaterol hydrochloride  2                                                   Total                    148                                                  ______________________________________                                    

Procaterol hydrochloride is dissolved in the above adhesive agent ofemulsion type and then the remaining components are added theretosuccessively and the mixture is stirred. Thereafter, the obtainedmixture is spread over a releasing paper in an amount of 100 g/m²(weight after dried) and dried. A polyethylene film is laminated ontothe dried adhesive agent and the laminate product is cut into a desiredsize to give an external preparation for application to the skin(containing 200 μg/cm² of procaterol hydrochloride).

COMPARATIVE EXAMPLE 2

    ______________________________________                                        [Component]             [% (w/w)]                                             ______________________________________                                        Isobutylene-maleic anhydride copolymer                                                                20                                                    (trade name: Isoban-10 manufactured by                                        KURARAY CO. LTD.)                                                             Glycerol polyglycidyl ether                                                                             0.6                                                 Procaterol hydrochloride                                                                               1                                                    Glycerol                q.s.                                                  Total                   100                                                   ______________________________________                                    

The isobutylene-maleic anhydride copolymer is added to glycerol and themixture is stirred in a kneader at 55° C. for 50 minutes. Then, to themixture are added procaterol hydrochloride and glycerol polyglycidylether in this order. However, the isobutylene-maleic anhydride copolymeris not dissolved in glycerol and remained therein as a dispersion, andas a result, any shaped preparation for application to the skin can notbe obtained.

COMPARATIVE EXAMPLE 3

    ______________________________________                                        [Component]               [% (w/w)]                                           ______________________________________                                        Methyl vinyl ether-maleic anhydride                                                                     15                                                  copolymer (trade name: Gantrez, manufactured by                               G.A.F.)                                                                       Ethylene glycol diglycidyl ether                                                                          1.3                                               Procaterol hydrochloride   1                                                  Glycerol                  q.s.                                                Total                     100                                                 ______________________________________                                    

The methyl vinyl ether-maleic anhydride copolymer is added to glyceroland the mixture was stirred in a kneader at 60° C. for 40 minutes. Then,to the mixture are added procaterol hydrochloride and ethylene glycoldiglycidyl ether in this order. However, the methyl vinyl ether-maleicanhydride copolymer is not dissolved in glycerol and remained therein asa dispersion, and as a result, any shaped preparation for application tothe skin can not be obtained.

COMPARATIVE EXAMPLE 4

    ______________________________________                                        [Component]                [% (w/w)]                                          ______________________________________                                        Isobutylene-maleic anhydride ammonium                                                                    15                                                 copolymer (trade name: Isoban-110 manufactured by                             KURARAY CO. LTD.)                                                             Glycerol polyglycidyl ether                                                                                0.5                                              Procaterol hydrochloride    1                                                 Glycerol                   q.s.                                               Total                      100                                                ______________________________________                                    

The isobutylene-maleic anhydride ammoniumcopolymer is dissolved inglycerol at room temperature. To the solution are then added procaterolhydrochloride and glycerol poly-glycidyl ether in this order and themixture is stirred to give an adhesive base. Thereafter, the proceduresin Example 1 are repeated to give an external preparation forapplication to the skin (containing 200 μg/cm² of procaterolhydrochloride).

COMPARATIVE EXAMPLE 5

    ______________________________________                                        [Component]             [% (w/w)]                                             ______________________________________                                        Methyl vinyl ether-maleic anhydride                                                                   15                                                    copolymer (trade name: Gantrez, manu-                                         factured by G.A.F.)                                                           Ethylene glycol diglycidyl ether                                                                        0.5                                                 Procaterol hydrochloride                                                                               1                                                    Water                   40                                                    Glycerol                q.s.                                                  Total                   100                                                   ______________________________________                                    

The methyl vinyl ether-maleic anhydride copolymer is dissolved inglycerol with heating at 100° C. To the solution are then addedprocaterol hydrochloride, ethylene glycol diglycidyl ether in this orderand the mixture is stirred to give an adhesive base. Thereafter, theprocedures in Example 1 are repeated to give an external preparation forapplication to the skin (containing 200 μg/cm² of procaterolhydrochloride).

EXPERIMENT 1

The skin taken from rat abdomen was put in a Franz diffusion cell andeach sample punched into a circular shape with 1.7 cm diameter(containing 227 μg of procaterol hydrochloride) was adhered to the ratskin in the diffusion cell (n=7). Using pH 7.0--phosphate buffer in areceptor, an amount of procaterol hydrochloride which permeated throughthe skin after a fixed time was measured by HPLC. The results are shownin FIG. 1.

EXPERIMENT 2

After anesthetizing dogs weighing 10 kg with pentobarbital, hair wasremoved at the abdomen and thereto was adhered the sample from Examples1 to 3 (2×2 cm² ; containing 400 μg of procaterol hydrochloride) or fromComparative Example 1 (2×2 cm² ; containing 800 μg of procaterolhydrochloride). The bronchodilating activity was determined from a rateof inhibition to an increase of ventilation overflow by an intravenousadministration of histamine (5 μg/kg), using the Konzett-Rossler method.The results are shown in FIG. 2.

EXPERIMENT 3

During the procedure in Experiment 2, blood was also taken from dogs andthe cAMP level in their blood was measured by the EIA method. It isgenerally known that the formation of cAMP is promoted by the β-acceptorstimulating activity and the concentration of cAMP is directlyproportional to blood level of β-acceptor stimulating agonist. Theresults are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Adhesion   Example        Comp. Example                                       Time (hr)  1      2        3    1                                             ______________________________________                                        0          11.4   16.5     10.9 10.5                                            0.5      26.7   23.3     27.8 18.8                                          1          38.5   33.5     43.2 19.0                                          3          39.    38.0     53.6 23.4                                          6          38.7   36.2     52.6 21.7                                                           Unit: pmol/ml                                                ______________________________________                                    

As is clear from the results of the above Experiments, it was found thatthe preparation for application to the skin of the present inventionshowed more excellent delivery, blood level and exhibition of activityof procaterol than those of the conventional emulsion type preparationfor application to the skin.

We claim:
 1. A procaterol-containing preparation for application to theskin which comprises a drug-retaining layer provided on a support,wherein said drug-retaining layer is a substantially water-free adhesivegel consists essential of 1 to 20% by weight of polyacrylic acid, acrosslinking agent selected from the group consisting of aluminumchloride, aluminum sulfate, aluminum potassium sulfate, ammoniumaluminum sulfate, magnesium aluminate silicate, magnesium aluminatemetasilicate, and dihydroxy aluminum acetate, 50 to 95% by weight of atleast one lower alcohol or polyvalent alcohol, and 0.1 to 5% by weightof procaterol, or a pharmaceutically acceptable salt thereof.
 2. Theprocaterol-containing preparation for application to the skin of claim 1wherein said adhesive gel contains 1 to 20% by weight of saidpolyacrylic acid, 0.01 to 7% by weight of said crosslinking agent, and50 to 95% by weight of said lower alcohol or polyvalent alcohol.
 3. Theprocaterol-containing preparation for application to the skin of claim 1wherein said adhesive gel contains 3 to 15% by weight of saidpolyacrylic acid, 0.01 to 5% by weight of said crosslinking agent, and55 to 90% by weight of said lower alcohol or polyvalent alcohol.
 4. Theprocaterol-containing preparation for application to the skin of claim 1wherein said crosslinking agent is selected from the group consisting ofan aluminum salt and a magnesium salt; said lower alcohol or polyvalentalcohol is selected from the group consisting of a lower alcohol, alower alkylene glycol, poly(lower)alkylene glycol and glycerol.
 5. Theprocaterol-containing preparation for application to the skin of claim 2wherein said crosslinking agent is selected from the group consisting ofan aluminum salt and a magnesium salt; said lower alcohol or polyvalentalcohol is selected from the group consisting of a lower alcohol, alower alkylene glycol, poly(lower)alkylene glycol and glycerol.
 6. Theprocaterol-containing preparation for application to the skin of claim 3wherein said crosslinking agent is selected from the group consisting ofan aluminum salt and a magnesium salt; said-lower alcohol or polyvalentalcohol is selected from the group consisting of a lower alcohol, alower alkylene glycol, poly(lower)alkylene glycol and glycerol.
 7. Theprocaterol-containing preparation for application to the skin of claim 4wherein said crosslinking agent is selected from the group consisting ofaluminum chloride, aluminum sulfate, aluminum potassium sulfate,ammonium aluminum sulfate, magnesium aluminate silicate, magnesiumaluminate metasilicate, and dihydroxy aluminum acetate; said loweralcohol is selected from the group consisting of ethanol and propanol;said polyvalent alcohol is selected from the group consisting ofethylene glycol, propylene glycol, 1,3-butanediol,3-methyl-1,3-butanediol, polyethylene glycol, polypropylene glycol andglycerol.
 8. The procaterol-containing preparation for application tothe skin of claim 5 wherein said crosslinking agent is selected from thegroup consisting of aluminum chloride, aluminum sulfate, aluminumpotassium sulfate, ammonium aluminum sulfate, magnesium aluminatesilicate, magnesium aluminate metasilicate, and dihydroxy aluminumacetate; said lower alcohol is selected from the group consisting ofethanol and propanol; said polyvalent alcohol is selected from the groupconsisting of ethylene glycol, propylene glycol, 1,3-butanediol,3-methyl-1,3-butanediol, polyethylene glycol, polypropylene glycol andglycerol.
 9. The procaterol-containing preparation for application tothe skin of claim 6 wherein said crosslinking agent is selected from thegroup consisting of aluminum chloride, aluminum sulfate, aluminumpotassium sulfate, ammonium aluminum sulfate, magnesium aluminatesilicate, magnesium aluminate metasilicate, and dihydroxy aluminumacetate; said lower alcohol is selected from the group consisting ofethanol and propanol; said polyvalent alcohol is selected from the groupconsisting of ethylene glycol, propylene glycol, 1,3-butanediol,3-methyl-1,3-butanediol, polyethylene glycol, polypropylene glycol andglycerol.
 10. The procaterol-containing preparation for application tothe skin of claim 1, 2 or 3 wherein said crosslinking agent is selectedfrom the group consisting of magnesium aluminate metasilicate, dihydroxyaluminum acetate and aluminum potassium sulfate, and said polyvalentalcohol is selected from the group consisting of propylene glycol andglycerol.
 11. A procaterol-containing preparation for application to theskin which comprises a drug-retaining layer provided on a support,wherein said drug-retaining layer is a substantially water-free adhesivegel consists essential of 1 to 20% by weight of polyacrylic acid, acrosslinking agent selected from the group consisting of aluminumchloride, aluminum sulfate, aluminum potassium sulfate, ammoniumaluminum sulfate, magnesium aluminate silicate, magnesium aluminatemetasilicate, and dihydroxy aluminum acetate, a sequestering agent, 50to 95% by weight of at least one lower alcohol or polyvalent alcohol,and 0.1 to 5% by weight of procaterol, or a pharmaceutically acceptablesalt thereof.
 12. The procaterol-containing preparation for applicationto the skin of claim 11 wherein said adhesive gel contains 1 to 20% byweight of said polyacrylic acid, 0.01 to 7% by weight of saidcrosslinking agent, 0.001 to 0.1% by weight of said sequestering agentand 50 to 95% by weight of said lower alcohol or polyvalent alcohol. 13.The procaterol-containing preparation for application to the skin ofclaim 11 wherein said adhesive gel contains 3 to 15% by weight of saidpolyacrylic acid, 0.01 to 5% by weight of said crosslinking agent, 0.001to 0.1% by weight of said sequestering agent and 55 to 90% by weight ofsaid lower alcohol or polyvalent alcohol.
 14. The procaterol-containingpreparation for application to the skin of claim 11 wherein saidcrosslinking agent is selected from the group consisting of an aluminumsalt and a magnesium salt; said sequestering agent is a chelating agent;said lower alcohol or polyvalent alcohol is selected from the groupconsisting of a lower alcohol, a lower alkylene glycol,poly(lower)alkytene glycol and glycerol.
 15. The procaterol-containingpreparation for application to the skin of claim 12 wherein saidcrosslinking agent is selected from the group consisting of an aluminumsalt and a magnesium salt; said sequestering agent is a chelating agentcapable of forming a complex with a heavy metal or a heavy metal ion;said lower alcohol or polyvalent alcohol is selected from the groupconsisting of a lower alcohol, a lower alkylene glycol,poly(lower)alkylene glycol and glycerol.
 16. The procaterol-containingpreparation for application to the skin of claim 13 wherein saidcrosslinking agent is selected from the group consisting of an aluminumsalt and a magnesium salt; said sequestering agent is a chelating agentcapable of forming a complex with a heavymetal or a heavy metal ion;said lower alcohol or polyvalent alcohol is selected from the groupconsisting of a lower alcohol, a lower alkylene glycol,poly(lower)alkylene glycol and glycerol.
 17. The procaterol-containingpreparation for application to the skin of claim 14 wherein saidcrosslinking agent is selected from the group consisting of aluminumchloride, aluminum sulfate, aluminum potassium sulfate, ammoniumaluminum sulfate, magnesium aluminate silicate, magnesium aluminatemetasilicate, and dihydroxy aluminumacetate; said sequestering agent isselected from the group consisting of EDTA, a pharmaceuticallyacceptable salt of EDTA, polyphosphoric acid and a pharmaceuticallyacceptable salt of polyphosphoric acid; said alcohol is selected fromthe group consisting of ethanol and propanol; said polyvalent alcohol isselected from the group consisting of ethylene glycol, propylene glycol,1,3-butanediol, 3-methyl-1,3-butanediol, polyethylene glycol,polypropylene glycol and glycerol.
 18. The procaterol-containingpreparation for application to the skin of claim 15 wherein saidcrosslinking agent is selected from the group consisting of aluminumchloride, aluminum sulfate, aluminum potassium sulfate, ammoniumaluminum sulfate, magnesium aluminate silicate, magnesium aluminatemetasilicate, and dihydroxy aluminum acetate; said sequestering agent isselected from the group consisting of EDTA, a pharmaceuticallyacceptable salt of EDTA, polyphosphoric acid and a pharmaceuticallyacceptable salt of polyphosphoric acid; said lower alcohol is selectedfrom the group consisting of ethanol and propanol; said polyvalentalcohol is selected from the group consisting of ethylene glycol,propylene glycol, 1,3-butanediol, 3-methyl-1,3-butanediol, polyethyleneglycol, polypropylene glycol and glycerol.
 19. The procaterol-containingpreparation for application to the skin of claim 16 wherein saidcrosslinking agent is selected from the group consisting of aluminumchloride, aluminum sulfate, aluminum potassium sulfate, ammoniumaluminum sulfate, magnesium aluminate silicate, magnesium aluminatemetasilicate, and dihydroxy aluminum acetate; said sequestering agent isselected from the group consisting of EDTA, a pharmaceuticallyacceptable salt of EDTA, polyphosphoric acid or a pharmaceuticallyacceptable salt of polyphosphoric acid; said lower alcohol is selectedfrom the group consisting of ethanol and propanol; said polyvalentalcohol is selected from the group consisting of ethylene glycol,propylene glycol, 1,3-butanediol, 3-methyl-1,3-butanediol, polyethyleneglycol, polypropylene glycol and glycerol.
 20. The procaterol-containingpreparation for application to the skin of claim 11, 12 or 13 whereinsaid crosslinking agent is selected from the group consisting ofmagnesium aluminate metasilicate, dihydroxy aluminum acetate andaluminum potassium sulfate, said polyvalent alcohol is selected from thegroup consisting of propylene glycol and glycerol, and said sequesteringagent-is EDTA 2Na.
 21. The procaterol-containing preparation forapplication to the skin of claim 11 which further comprises a drugabsorption-promoting agent.
 22. The procaterol-containing preparationfor application to the skin of claim 12 which further comprises 0.1 to20% by weight of an absorption-promoting agent.
 23. Theprocaterol-containing preparation for application to the skin containingprocaterol of claim 20 which further comprises 0.1 to 15% by weight ofan absorption-promoting agent selected from the group consisting ofN,N-diethyl-m-toluamide and N,N-dimethylacetamide.